The need for developing new and effective treatment modalities for cardiac regeneration is expanding, as cardiac disease continues to take more human lives than all cancer combined. Cardiac tissue engineering has great capacity to enhance tissue repair and to provide realistic tissue models for studying cardiac regeneration. The difficulties arise from our limited ability to faithfully regenerate at multiple scales the anisotropic structural and functional properties of native heart muscle. We propose a radically novel strategy to reach this goal, by forming a branching vascular network perfusable with blood and using this network as a template to build cardiac tissue. Our hypothesis is that the synergistic application of topographical cues (provided by a groove and ridge scaffold made of native heart matrix hydrogen), molecular regulatory factors (incorporated in hydrogel and secreted by supporting cells) and in vitro conditioning (electromechanical and hypoxic) of cardiomyocytes derived from human induced pluripotent stem cell (iPSC) will recapitulate a native-like cardiac niche and lead to the formation of functional tissue. We propose to rigorously test this hypothesis in quantitative studies of cardiac regeneration, in vitro and in vivo. Our mai interest is in the factors and mechanisms that improve the maturity, survival and function of engineered cardiac tissue. Three specific aims will be pursued. Aim 1 is to establish a branching human vascular network by directed capillary outgrowth within an artery/vein system. Aim 2 is to engineer human cardiac muscle around the vascular network, mature its function, and enhance its survival under hypoxic conditions. Aim 3 is to functionally evaluate vascularized cardiac grafts in an animal model of cardiac ischemia. In all three aims, the focus is on biophysical control of cardiac regeneration by modulation of maturation, survival and functional assembly of human cells into vascularized cardiac muscle. We believe that this work has significance for quantitative biological research and the development of practical tissue-engineering modalities for treating heart disease.